Case ReportUnloading of Right Ventricle and ClinicalImprovement after Ultrasound-Accelerated Thrombolysis inPatients with Submassive Pulmonary Embolism
1 Department of Cardiology, Providence Hospital and Medical Center, 16001 W Nine Mile Road, Southfield, MI 48075, USA2Department of Internal Medicine, Providence Hospital and Medical Center, 16001 W Nine Mile Road, Southfield, MI 48075, USA
Correspondence should be addressed to Sachin Kumar Jain; [email protected]
Received 6 May 2014; Accepted 17 June 2014; Published 1 July 2014
Acute pulmonary embolism (PE) can be devastating. It is classified into three categories based on clinical scenario, elevatedbiomarkers, radiographic or echocardiographic features of right ventricular strain, and hemodynamic instability. Submassive PEis diagnosed when a patient has elevated biomarkers, CT-scan, or echocardiogram showing right ventricular strain and no signsof hemodynamic compromise. Thromboemboli in the acute setting increase pulmonary vascular resistance by obstruction andvasoconstriction, resulting in pulmonary hypertension. This, further, deteriorates symptoms and hemodynamic status. Studieshave shown that elevated biomarkers and right ventricular (RV) dysfunction have been associated with increased risk of mortality.Therefore, aggressive treatment is necessary to “unload” right ventricle. The treatment of submassive PE with thrombolysis iscontroversial, though recent data have favored thrombolysis over conventional anticoagulants in acute setting. The most fearedcomplication of systemic thrombolysis is intracranial or major bleeding. To circumvent this problem, a newer and safer approachis sought. Ultrasound-accelerated thrombolysis is a relatively newer and safer approach that requires local administration ofthrombolytic agents. Herein, we report a case series of five patients who underwent ultrasound-accelerated thrombolysis withnotable improvement in symptoms and right ventricular function.
1. Introduction
Pulmonary embolism (PE) and deep venous thrombosis(DVT) are a major cause of morbidity and mortality in theUnited States and are the leading cause of death in hospitalstoday. Pulmonary embolism is a blood clot which originatesin the deep venous system of the lower exterminates andtravels to the lungs where it lodges in the main pulmonaryartery or surrounding branches. The result is an obstructionof blood flow that ordinarily would be oxygenated andreturned to the systemic circulation. Given the nature ofthe venous system blood flow, there is low pressure andslowmoving increasing the probability of formation of bloodclot [1]. Pulmonary embolism or venous thrombosis is adevastating diagnosis and is referred to as a silent killer.
It affects over a million people every year with 100,000 to200,000 of these cases fatal. Early diagnosis is the key toimproved survival rates. Of the fatal cases, 20% die beforetheir initial diagnosis or days later [2]. Once the diagnosis ofPE is made, it should be classified further into one of threecategories: (1) low-risk PE, (2) submassive PE, and (3)massivePE. The diagnosis of low-risk, submassive, and massive PEis made based on clinical presentation, abnormal biomark-ers, echocardiography/imaging evidence, and hemodynamicinstability.
For each category, themanagement significantly differs. Asubmassive PE is diagnosed when there is a characteristic ofan embolus/emboli causing right ventricular strain withoutsignificant hypotension (systolic blood pressure <90mmHg)and elevated biomarkers. When there is an evidence of shock
Hindawi Publishing CorporationCase Reports in MedicineVolume 2014, Article ID 297951, 8 pageshttp://dx.doi.org/10.1155/2014/297951
2 Case Reports in Medicine
(systolic blood pressure less than 90mmHg), the patient hasmassive PE [3]. Thrombolytic therapy is recommended forpatients with massive PE (assuming no contraindications);however, the use of thrombolytic drug is controversial in sub-massive PE [4]. Even though it is used with the best intentionin such patient, the risk of bleeding should not be overlooked.Thrombolytic agents have been shown to increase risk ofmajor bleeding, nonmajor bleed, and intracranial bleedingcompared to heparin [5]. Therefore, alternative strategies aredeveloped. An ultrasound-accelerated thrombolysis (UAT)is a relatively newer strategy that is intended to minimizerisk of bleeding and improve outcomes. The UAT uses high-frequency, low power ultrasound wave that disrupts fibrinstrands and makes the clot more permeable to a fibrinolyticagent.The fibrinolytic agent is delivered directly into the pul-monary artery along with intravenous anticoagulant. Oncethe fibrinolytic agent binds to the clot, it does not migrateinto circulatory system [6]. The early goals of the treatmentare preventing the progression of clot burden, improvinghemodynamic status, and relief from the symptoms andlong-term complications such as chronic thromboembolicpulmonary hypertension (CTEPH). We believe that UATcould be effective against acute burden on the right ven-tricle, even in the cases of acute on chronic pulmonaryembolism, and will improve hemodynamic status and reliefof symptoms. Hopefully, this will prevent CTEPH as systemicanticoagulants will take over. We report a case series offive cases that were treated with UAT demonstrating clinicalimprovement in the acute setting. All five patients gaveinformed consent before treating them with this alternativeapproach.
2. Case 1
A38-year-oldAfricanAmericanmale was sent to the hospitalby his primary care physician office after the patient com-plained of progressively worsening shortness of breath overthe past two days. The patient has medical history of asthmaand gout, but he denied this episode as his typical asthmaattack. He stated that the symptoms worsen during night.Additionally, he complained of 1-month history of left lowerextremity swelling after he had 9-10 hours long, nonstop roadtrip. He denied chest pain, palpitations, or lightheadedness.His initial vital signs were respiratory rate of 25 breaths perminute, blood pressure of 151/111mmHg, heart rate of 108beats per minute, oxygen saturation of 94% on room air,temperature of 97.7 Fahrenheit, and body mass index of 44.The patient’s physical exam was remarkable for tachycar-dia, S3 gallop, and slight wheezing. His electrocardiogramshowed sinus tachycardia, S1Q3T3 pattern, and incompleteright bundle branch block. His initial troponin, Pro-BNP,and D-Dimer were 1.09 ng/mL (nomral: 0–0.10 ng/mL),6853 pg/mL (normal: 50–92 pg/mL), and 4060 ng/mL (nor-mal: 200–232 ng/mL), respectively. The patient underwentCT-thorax, which showed emboli within the right lower andmiddle lobe arteries. Also, there was a 41mmdilatation of themain pulmonary artery, cardiomegaly with small pericardialeffusion and mild pulmonary edema. His lower extremity
ultrasoundwithDoppler showed acute-to-subacute occlusivethrombus extending into the left common femoral vein.His echocardiography showed right ventricular enlargementwith right-to-left ventricle ratio (RV/LV) greater than 1,dyskinesia of the RV (Figure 1), and right ventricle systolicpressure (RVSP) of 75mmHg. He also had mild left ventric-ular enlargement and ejection fraction of 20%.
Due to the significant right ventricular strain and elevatedtroponin, a submassive PEwas diagnosed.The patient under-went UAT (1mg/hr of alteplase was delivered for 12 hoursvia the catheter in Figure 1) in the right pulmonary arteryand he continued to receive intravenous heparin; he wasmedically managed under Intensive Care Unit care. As hishospital course progressed, the patient became asymptomaticwith rapid improvement in next two days. He could ambulatewithout the need for oxygen supplement. An echocardio-gram prior to discharge showed improvement in the rightventricular function and RV/LV1. At this time, the RVSPwas 50mmHg. He was discharged home with Coumadin.His follow-up CT scan at 6 months demonstrated persistentemboli in the right lower pulmonary artery despite theoral anticoagulant. The patient was referred for surgicalthrombectomy. Refer to Table 1 for data summary.
3. Case 2
A 40-year-old African American male came to our hospitalafter he had undergone a syncopal episode. His past med-ical history includes deep vein thrombosis, chronic lowerextremity lymphedema, and diabetes. The patient deniedtrauma, recent travelling, and sedentary lifestyle. He alsodenies history of hypercoagulable state. Upon arrival, hisvital signs were respiratory rate of 30 breaths per minute,blood pressure of 124/92mmHg, heart rate of 125 beats perminute, oxygen saturation of 98% on a nonrebreather mask,and temperature of 97.7 Fahrenheit. His physical exam wasremarkable for anxious middle-aged man with tachycardia,jugular venous pressure of 15 cm, and venous stasis in thelower extremities. The electrocardiogram shows tachycardia,S1Q3T3 pattern, and poor R-wave progression in the ante-rior precordial leads. An initial laboratory workup revealedtroponin level of 0.02 ng/mL (normal: 0–0.10 ng/mL), pro-BNP of 149 pg/mL (normal: 50–92 pg/mL), and D-Dimer at5000 ng/mL (normal: 200–232 ng/mL). He underwent CT-thorax which showed extensive thrombus in both distalmain pulmonary arteries with small component of mainpulmonary artery saddle thrombus (Figure 2). The rightlower extremity ultrasound with Doppler showed occlusivethrombus extending from the right popliteal vein to rightcommon femoral vein.
An emergent echocardiogram was obtained, whichshowed marked dilatation of the right ventricle, RV/LV >1, and severe right ventricular global hypokinesis (Figure 2).The RVSP was 70mmHg. A submassive PE was diagnosedand the patient was taken to cardiac catheterization lab forUAT catheter placement; heparin and 1mg/hr of alteplasewere delivered via each catheter for 10 hours. Ten dayslater, a repeat transthoracic echocardiogram showed normal
Case Reports in Medicine 3
(a) (b)
(c) (d)
Figure 1: (a) The parasternal short axis view from echocardiography shows dilatation of the right ventricle (green line). (b) The CT-thoraxwith contrast filling defect in the right main pulmonary artery confirms the diagnosis of pulmonary embolism. (c)The fluoroscopy illustratesthe placement of ultrasound-accelerated thrombolysis catheter in the right main pulmonary artery. (d)The improvement in right ventricularfunction after UAT (green asterisk).
ejection fraction, RV/LV < 1, and minimal paradoxicalseptal motion (Figure 2) and RVSP of 62mmHg. The patientno longer complained of dyspnea or lightheadedness. Thepatient was sent home on rivaroxaban and other homemedications. Refer to Table 1 for data summary.
4. Case 3
A38-year-oldAfricanAmerican female went to a communityhospital for difficulty in breathing. A week before, she had anacute onset of difficulty in breathing, which was associatedwith occasional lightheadedness. Later, she had difficultywithperforming her activity of daily leaving due to the shortnessof breath. The patient has history of iron deficiency anemiaand depression. She was on birth control pills, which shehad been taking for the past 18 years. She is neither smokernor substance abuser. At the time of presentation, she deniedchest pain, lightheadedness, diaphoresis, headache, or dizzi-ness. The initial vitals were blood pressure of 129/49mmHg,
respiratory rate of 15 breaths per minute, pulse rate of 75beats per minute, and oxygen saturation of 95% on roomair. She was afebrile. The cardiopulmonary, neurologic, andmusculoskeletal exam was unremarkable. The laboratoryworkup did not reveal any electrolytes abnormalities; how-ever, her pro-BNP was 1193 pg/mL (normal: 50–92 pg/mL)and troponin was 0.02 ng/mL (normal: 0–0.10 ng/mL). Anelectrocardiogram showed normal sinus rhythmwith T-waveinversions in inferior leads and V1-V3 without ST-segmentchanges. A CT-thorax showed large bilateral pulmonaryemboli in the pulmonary arteries. At this time, the patientwas transferred to our hospital for further management. Theechocardiogram revealed preserved left ventricular ejectionfraction, hypokinetic RV with RV/LV > 1 and severe pul-monary hypertension (right ventricular systolic pressure of73mmHg) (Figure 3). A lower extremity ultrasound withDoppler showed acute occlusive and nonocclusive deep veinthrombosis in left popliteal and right common femoral vein,respectively.
CT-scan findings Right middle andlower lobe emboli Saddle emboli
Bilateral emboliwithin main
pulmonary arteries
Bilateral emboliwithin main
pulmonary arteriesSaddle emboli
Echocardiogram(RVSP in mmHg)
Hypokinetic RVenlargement (75),
RV/LV > 1
Markedly dilatedand hypokinetic
RV (70), RV/LV > 1
RV/LV > 1, severepulmonary
hypertension (73),and hypokinetic RV
Right ventricularstrain, straighteningof the septum (57),
RV/LV > 1
Hypokinesia of rightventricular free wall(60), RV/LV > 1
Alteplase amount(per PA) 12 10 13 12 6
Follow-upechocardiogram(RVSP in mmHg)
Improved functionof the right ventricle(50), RV/LV < 1
Mild RV dyskinesia(62), RV/LV < 1
No RV strain orpulmonary
hypertension (35),RV/LV < 1
Mildly depressed RVfunction (40),RV/LV < 1
Resolution of RVhypokinesia (45),
RV/LV < 1
Presenting symptoms atthe time of discharge Resolved Resolved Resolved Resolved Resolved
DVT = deep vein thrombosis; BNP = brain-natriuretic peptide; sPAP = systolic pulmonary artery pressure during right heart catheterization; RV = rightventricle; LV = left ventricle; PA = pulmonary artery; RVSP = right ventricular systolic pressure.
(a) (b)
(c) (d)
Figure 2: (a) The green triangle is located in the markedly dilated right ventricle. (b) The red arrows point at saddle emboli. (c) Theechocardiogram shows improvement in the size of right ventricle. (d) The fluoroscopy confirms the placement of the UAT catheter in bothmain pulmonary arteries (blue arrows).
Case Reports in Medicine 5
(a) (b)
Figure 3: (a) The red square is in the right ventricle that is markedly dilated compared to left ventricle dimension. (b) The image shows thedecrease in size of the right ventricle after the UAT (red square).
These findings were suggestive of submassive PE, whichwas treated with ultrasound accelerated thrombolysis. Theright heart catheterization showed systolic pulmonary arterypressure of 51mmHg. The catheters were placed in both pul-monary arteries and 13mg of alteplase, along with heparin,was delivered over 16 hours with heparin drip. The patienttolerated the thrombolysis procedure without complication.The patient was discharged on oral rivaroxaban after theresolution of presenting symptoms. Three days later, theechocardiogram showed left ventricular ejection fractionof 65%, without the evidence of right ventricular strain(RV/LV < 1) or elevated right ventricle systolic pressure(Figure 3). The RVSP was 35mmHg. Refer to Table 1 for datasummary.
5. Case 4
A 77-year-old African American female came to our hos-pital complaining of shortness of breath. The patient wasexperiencing severe left-sided abdominal pain for the pasttwo weeks. It was not associated with any alleviating oraggravating factors. On the day of presentation, she becamelightheaded and experience shortness of breath. The dis-comfort was associated with two episodes of nonbloodyemesis and left-sided pleuritic chest pain. She did nothave any retrosternal chest pain, diaphoresis, or syncopalepisode. She was, additionally, complaining of right lowerleg cramping. Her medical history included hypertension,diabetes, and deep vein thrombosis, which was treated withan oral anticoagulant for six months. The initial vitals wereblood pressure of 125/62mmHg, heart rate of 92 beatsper minute, respiratory rate of 18 breaths per minute, andoxygen saturation of 99% on room air; she was afebrile.The cardiopulmonary exam was unremarkable. The initialtroponin level was 0.02 ng/mL (normal: 0–0.10 ng/mL), eighthours apart. The pro-BNP level was at 7511 pg/mL (nor-mal: 50–92 pg/mL). An electrocardiogram showed normalsinus rhythm without significant findings. A CT-chest withcontrast showed diffuse bilateral pulmonary emboli in theright and left main pulmonary arteries and straightening ofthe interventricular septum suggestive of right ventricular
strain (Figure 4). The echocardiogram showed preservedejection fraction, hypokinetic RV, mild pulmonary hyper-tension (RVSP of 49mmHg), and RV/LV >1 (Figure 4). Theultrasound with Doppler of the lower extremities did notshow deep vein thrombosis.
The patient was diagnosed with submassive PE, and shewas decided to be treated with UAT. The UAT catheters wereplaced in both arteries and local alteplase was administeredfor 12mg with heparin over 12 hours after receiving 2mg ofbolus. There were no peri- or postprocedural complications.The next day, the patient experienced marked improvementin dyspnea. Next day, a repeated echocardiography showedpreserved ejection fraction with mildly depressed right ven-tricular function with RV/LV <1 (Figure 4) and RVSP of40mmHg. The patient was discharged on oral rivaroxaban.Refer to Table 1 for data summary.
6. Case 5
A 72-year-old African American female came to the hospitalcomplaining of shortness of breath.The patient stated that thedyspnea started to progress over three days limiting her activ-ity of daily living.The symptomswouldworsenwith exertion.She denied any chest pain, lightheadedness, diaphoresis, nau-sea, or vomiting. Her medical history includes hypertension,chronic obstructive lung disease, and dyslipidemia. At thetime of presentation, the vital signs were blood pressure of136/66mmHg, heart rate of 75 beats per minute, respiratoryrate of 18 breaths per minute, oxygen saturation of 95% onroomair, andno fever.The cardiopulmonary, extremities, andneurologic exam was unremarkable. An electrocardiogramrevealed normal sinus rhythm without significant abnor-mal findings. An initial laboratory workup showed pro-BNP level of 603 pg/mL (normal: 50–92 pg/mL), troponinof 0.02 ng/dL (0–0.10 ng/mL), and D-Dimer at 2072 ng/mL(normal: 200–232 ng/mL). A CT-scan of thorax with contrastrevealed saddle pulmonary embolus of the right and leftmain pulmonary artery with extensive emboli (Figure 5). Anemergent echocardiography showed normal ejection fractionwith hypokinesia of right ventricular free wall. There wasan evidence of moderate pulmonary hypertension (RVSP of
6 Case Reports in Medicine
(a) (b)
(c)
Figure 4: (a) The right ventricle is dilated and the septum is flattened (green asterisk). (b) The red arrows point at multiple bilateral emboli.(c) The image shows improvement in right ventricle dimension after the treatment.
58mmHg). Based on these findings, a submassive PE wasdiagnosed (Figure 5). The ultrasound with Doppler of thelower extremity showed no evidence of deep vein thrombosis.
For the treatment, the patient was taken for right heartcatheterization for the placement of UAT in the main pul-monary arteries. The UAT catheters were placed in bothpulmonary arteries, and heparin and 0.5mg/hr of alteplasewere delivered to each artery for 12 hours. There wereno complications. Two days later, repeated echocardiogramshowed marked improvement in right ventricle function(RV/LV < 1) and right ventricle systolic pressure (45mmHg)(Figure 5). The patient denied exertional dyspnea and couldambulate without limitations. She was discharged to homewith oral rivaroxaban. Refer to Table 1 for data summary.
7. Discussion
Once the diagnosis of pulmonary embolism is confirmed, thetreatment strategies should be based on the classification ofpulmonary embolism.Apulmonary embolismwith hemody-namic compromise should be treated more aggressively withfibrinolytics (if there are no contraindications and acceptablebleeding risk) or surgical embolectomy [7]. In contrast,patients with PE and without any evidence of hemodynamiccompromise or right ventricular strain are classified as low-risk PE [3].
A submassive PE is classified based on elevated car-diac biomarkers (e.g., Pro-BNP and troponin) and rightventricular strain without hemodynamic compromise [8].Studies have shown that patients with right ventriculardysfunction, elevated troponin, and NT-pro-BNP levels havebeen associated with increased rate of mortality comparedto baseline or normal values, respectively [9–11]. In acutesetting of pulmonary embolism, increase in pulmonary vas-cular resistance results in elevated right ventricular systolicpressure up to 40mmHg (nearly doubles from the baseline).Some patients with higher right ventricular systolic pressurethan 40mmHg may be attributable to coexisting pulmonaryhypertension [12], including acute or chronic thrombus. Thenet effect is dilatation and dyskinesia of right ventricle, tri-cuspid regurgitation resulting in right ventricular failure.Thisleads to right ventricular ischemia/microinfarction (the causeof troponemia) and pressure overload (elevated pro-BNP)[13, 14]. The early compensation of reduced blood pressurefrom RV failure masks the impeding shock [12]. Therefore,patients with high-index of clinical suspicion for submassivePE should be evaluated with cardiac biomarker and imagingmodality to assess the right ventricle. The RV strain is bestassessed by emergent echocardiography. The characteristicfindings include RV dyskinesia and dilatation (sometimesexceeding the dimensions of left ventricle), flattening ofseptum (the right ventricle appears like alphabet letter “D”),paradoxical movement of septum towards left ventricle, and
Case Reports in Medicine 7
(a) (b)
(c)
Figure 5: (a)The echocardiogram shows dilated right ventricle (green line). (b)TheCT-scan shows an evidence of saddle emboli (red arrows).(c) There was a marked improvement in right ventricle size after the treatment (green line).
pulmonary hypertension [8]. Bases on these findings, anaggressive treatment plan should be formulated to avoid fatalcomplications.
The role of fibrinolytics is controversial in such patientsand anticoagulants are mainstay of treatment. The role offibrinolytics in submassive PE has been assessed inMAPPET-3 trial which has shown reduced in-patient mortality andclinical deterioration requiring escalation of therapy in fibri-nolytics plus heparin arm than heparin alone [15]. In anotherprospective trial, the use of fibrinolytics had advantage overheparin alone in reduction of pulmonary hypertension at6-month follow-up [16]. A recently published trial (>1000patients) has demonstrated that intermediate-risk PE patients(submassive PE) treated with fibrinolytics plus anticoagu-lant are less likely to have hemodynamic compromise thanplacebo group [17]. Despite the benefits of using fibrinolyticsin submassive PE, themost feared complication is fatal bleed-ing (e.g., intracranial or gastrointestinal bleeding).Therefore,less harmful yet effective alternative should be sought; theseinclude catheter-based, local administration of fibrinolyticagent, surgical embolectomy, and fragmentation or aspirationof the thrombus [8]. A surgical option is reserved for thosewho have contraindications or refractory to fibrinolytic agent[7].
Currently, ultrasound-accelerated thrombolysis (UAT) isan emerging option. It prevents hemolysis and mechanicalfragmentation of the emboli, which are the complications ofrheolytic-based mechanical fragmentation of the thrombus[6]. In comparison to systemic thrombolysis, UAT requiresless fibrinolytic agents, thus, a fewer chances of fatal bleeding.The efficacy of UAT against anticoagulant therapy has beenstudied in ULTIMA trial. The study showed statisticallysignificant reduction in right ventricular strain within 24hours in UAT plus heparin versus heparin alone groupwithout significant bleeding. In addition, there was markedreduction RV/LV ratio. The trial reported no major bleedingcomplications. The UAT was concluded to be superiorto heparin alone [18]. Another trial that is evaluatingthe role of UAT in submassive and massive PE is underinvestigation. When there is persistent vascular obstructionand vasoconstriction, CTEPH could result. It has shownfibrinolytics to reduce frequency of CTEPH [19], thoughthere is no published data on UAT and CTEPH. The limitedavailable data have shown that UAT is safer and has effectivemodality in comparison to an anticoagulant alone. To ourknowledge, there is no published data comparing UAT andother catheter-directed therapy or surgical embolectomy
8 Case Reports in Medicine
in submassive PE. Our cases suggest that ultrasound-accelerated thrombolysis can be effective in unloading ofthe right ventricle and decreasing pulmonary hypertension(decreasing right ventricle pressure load) in the acute settingwithout any bleeding complications from the fibrinolyticagent. Long-term anticoagulants and body hemostasis willtake over and may help dissolve the clot completely.
8. Conclusion
The case series demonstrates that UAT is associated withclinical improvement in the acute clinical setting withoutmajor bleeding complications, and it adds to current litera-ture. In patients with submassive PE and RVSP greater than40mmHg, UAT will relieve acute component.The long-termmanagement should be based on available guideline.
Conflict of Interests
The authors declare that there is no conflict of interestsregarding the publication of this paper.
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